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Nitric oxide in acute and chronic inflammation.

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Abstract

Nitric oxide (NO) is a signalling molecule formed when L-arginine is
converted to L-citrulline by the enzyme NO synthase (NOS. NOS exists as three
isoforms, ecNOS is constitutively expressed in endothelial cells and nNOS in
neuronal cells, while a third isoform (iNOS) is induced in response to
inflammatory stimuli and is capable of sustained production of high levels of NO.
NO produced in response to an inflammatory insult, has been shown by use of
NOS inhibitors to be detrimental during inflammation by producing the potent
oxidising agent peroxynitrite. However, iNOS knockout animals generally
produce a similar inflammatory profile to wild type controls. Hence, there is a
discrepancy between the effects of phamacological inhibition and gene deletion
of iNOS in vivo. Therefore, the aim of this thesis is to use a number of
approaches to modulate NO production in acute and chronic inflammatory
models and to assess the effects on the NOS pathway and other markers of the
inflammatory response.
In this thesis, it was established that iNOS protein expression and nitrite
formation was significantly elevated after injection of the inflammatory stimulus
in the carrageenin-induced pleurisy (RCIP), bovine serum albumin (BSA)-induced
pleurisy and methylated BSA-induced pleurisy in the rat, and a murine models
of croton oil-induced chronic granulomatous tissue of the air pouch (MCGTAP).
The majority of immunostaining was associated with migrating inflammatory cells.
NO production was modulated in acute and chronic models of inflammation using
NOS inhibitors and NSAIDs. Local injection of NOS inhibitors in the RCIP model
caused an increase in pro-inflammatory mediators, including superoxide,
histamine and PMN chemoattractants that resulted in an exacerbation of
inflammation. This was a result of inhibition of both eNOS and NOS at the
inflammatory site. In contrast, systemic inhibition of NOS reduced both
inflammatory cell influx and exudation into the pleural cavity. A similar inhibitory
ABSTRACT
result was obtained after NOS inhibition in the MCGTAP model. This antiinflammatory
effect was supported by experiments in mice whose iNOS gene had
been genetically deleted. Interestingly, oral aspirin administration significantly
elevated nitrite formation in both the RCIP and MCGTAP with a concomitant
decrease in inflammation. Further analysis demonstrated that aspirin was able
to elevate NO production in lipopolysaccharide induced J774 macrophages and
A23187 stimulated EA. hy926 endothelial cells, suggesting that both cell types
may be involved in the pharmacological actions of aspirin.
In conclusion, NO is a multi-functional free-radical which had
advantageous effects in the acute resolving model and detrimental effects in
chronic inflammation. Therefore, depending on the levels and micro-environment
in which it is produced NO can be either good or bad